A 10-Year Follow-up Affirms AREDS2 with Lutein Still Effective, Safe

Lutein and Zeaxanthin for eye health
Lutein and Zeaxanthin for eye health
AREDS2 with lutein and zeaxanthin is effective to slow AMD progression, without raising lung cancer risk for former smokers.

Following the Age-Related Eye Disease Study (AREDS), a supplement shown to reduce the risk of progression from intermediate to late age-related macular degeneration (AMD) by 25% during a 5-year period was launched. But an ingredient that, in 2001, demonstrated a protective effect — beta carotene — was found to nearly double risk for lung cancer, mostly in patients who formerly smoked. 

In 2013, the Age-Related Eye Disease Study 2 (AREDS2) evaluated ω-3 fatty acids and lutein with zeaxanthin as possible additions to the formulation. Now, after 10 years, a follow-up analysis demonstrates lutein’s benefit continued without raising the risk for lung cancer, offering assurance for clinicians, as published in JAMA Ophthalmology.

In AREDS2, a 5-year clinical trial, patients with intermediate AMD or late AMD in 1 eye were randomized to 4 treatment groups: lutein/zeaxanthin, ω-3 fatty acids, both lutein and ω-3, or placebo. A secondary analysis included patients who never smoked or those who quit smoking at least 1 year prior, randomized to receive either no beta carotene, or beta carotene along with low- or high-dose zinc. After AREDS2, the current 5-year telephone study enrolled existing participants who were mailed the new formulation with 10 mg lutein/2 mg zeaxanthin, vitamin C, vitamin E, copper, and zinc. This epidemiologic follow-up, from December 1, 2012 to December 31, 2018 comprises data on self-reported late AMD or lung cancer diagnosis, in many cases validated by medical records. 

Investigators conducted statistical analysis between November 2019 and March 2022. Of 4203 individuals in AREDS2, 3882 volunteered to take the reformulated supplements and receive telephone calls spaced 6 months apart. Participants were, on average, 72.0±7.7 years of age at baseline. Also, 673 of those receiving phone checks, plus 36 who were not called were offered in-clinic examinations near the conclusion of this follow-up.

In 10 years, 117 patients developed lung cancer. The odds ratio to contract lung cancer was 1.82 for those who had been randomized to beta carotene (95% CI, 1.06–3.12; P =.02). Most cases of lung cancer involved former smokers. In contrast, the odds ratio was significantly lower, 1.15, for individuals randomized to lutein/zeaxanthin (95% CI, 0.79–1.66; P =.46).

Of 6351 eyes, 3040 progressed to late AMD. Researchers used Kaplan-Meier probability to calculate advancement of disease in patients using lutein/zeaxanthin was 47.9% compared with 49.0% for those not taking this antioxidant. “The hazard ratio (HR) for progression to late AMD comparing lutein/zeaxanthin with no lutein/zeaxanthin was 0.91 (95% CI, 0.84–0.99; P =.02) and comparing ω-3 fatty acids with no ω-3 fatty acids was 1.01 (95% CI, 0.93–1.09; P =.91),” the analysis explains. The hazard ratio for progressing to late-stage AMD was also favorable for the lutein/zeaxanthin-only cohort compared with individuals taking beta carotene only (P =.02).

In addition to the post hoc design, a lack of ophthalmic images for all during this study was a limitation, because investigators could not determine long-term correlations between AREDS2 supplements and two individual AMD subtypes. Also, this sample was mostly well-educated and nourished, so results may not be generalizable. Conversely, a strong participation rate generated robust data. After 7.5 years, more than 1% were still using AREDS supplements, and 91% continued taking AREDS2 formulation.

Disclosure: This research was partially supported by Bausch + Lomb Corporation. Please see the original reference for a full list of disclosures.


Chew EY, Clemons TE, Agrón E, et al. Long-term outcomes of adding lutein/zeaxanthin and ω-3 fatty acids to the AREDS supplements on age-related macular degeneration progressionJAMA Ophthalmol. Published online June 2, 2022. doi:10.1001/jamaophthalmol.2022.1640